Chronic Obstructive Pulmonary Disease (COPD) is a disabling disorder that affects millions of people and is a leading cause of death in the U.S. and worldwide. Although smoking cessation can halt progression of early disease, once the disease becomes advanced, it may progress even with smoking cessation. Recent evidence suggests that progression of COPD is the result of dysregulation of cellular maintenance processes in the lung that result in apoptosis leading to emphysema. The complex interplay of oxidative stress, inflammatory cytokines, growth factors, and proteases promote this process leading to parenchymal destruction and airway remodeling. The thematic underpinning of this SCCOR is that understanding the processes leading to structural progression of COPD will lead to treatments that can halt clinical progression of the disease. The projects in this SCCOR explore key pathways that are involved in progression of COPD - novel anti-apoptotic properties of anti-proteases, genetic susceptibility to oxidative stress, the pro-inflammatory effects of particulate inhalation, and the pro-inflammatory stress of intermittent hypoxia. Innovative clinical therapeutic trials investigate anti-inflammatory agents and growth factor inhibitors, environmental controls, and mechanical support of nocturnal ventilation - all of which are promising treatments to stop progression of COPD. Highly focused basic proteomic research addresses the post-translational modification of alpha-1 anti-trypsin and highly focused genomic research addresses the role of the anti-oxidant regulatory gene Nrf2. The Hopkins SCCOR application represents a consortium of investigators with multidisciplinary expertise, and the common goal to translate basic research discoveries into direct benefit for patients with COPD. Supported by four interactive cores (Administration, Imaging, Patient Recruitment and Data Management, and Molecular Pathophysiology), the five human and animal projects will use state-of-the-art molecular approaches and novel phenotyping methods that will not only provide the deepest understanding of critical pathobiologic processes in COPD to date, but will define key pathways relevant to disease susceptibility and uncover new therapeutic approaches to modify the course of this disease INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Novel Protective Antiapoptotic Action of Alpha 1-Antitrypsin In Emphysema (Tuder, Rubin) DESCRIPTION (provided by applicant): Alveolar cell apoptosis represents one of the major pathobiological processes that account for the loss of alveolar septae and tissue destruction in emphysema. Our overall concept underlying this SCCOR proposal is that the interaction of inflammation and apoptotic cell destruction due to disruption of lung cellular maintenance determines the magnitude of lung destruction in chronic obstructive pulmonary disease (COPD). Although the prevailing paradigm of emphysema development in patients with alpha-1 antitrypsin (A1AT) deficiency emphasizes the role of A1AT as an elastase inhibitor, serine protease inhibitors (Serpins), including A1 AT, have broader biological effects beyond their classical action as protease inhibitors. It is our goal to identify novel biological roles of A1 AT that might enhance our understanding of the pathogenesis of alveolar cell injury leading to emphysema. We hypothesize that A1 AT prevents emphysema by binding to and inhibiting active caspase-3, leading to alveolar protection against apoptosis, a critical step of alveolar destruction in emphysema. This basic science project relies on an integrated approach involving the VEGF receptor blockade model of emphysema and adeno-associated virus transduction of human A1AT in vivo, and on focused mechanistic studies using cell cultures and cellfree systems to probe for the interaction of A1 AT and caspase-3. We have developed state of the art experimental assessment of emphysema lungs, based on standardized morphometry, lung imaging, pulmonary function tests (with the support of Molecular Pathophysiology Core D), and end points related to apoptosis, oxidative stress, and the proapoptotic lipid ceramide. Our specific aims are (1) To demonstrate that A1 AT prevents the development of emphysema in mice by blocking apoptosis, and thus reducing oxidative stress and ceramide levels. (2) To determine whether A1 AT protects pulmonary endothelial cells from apoptosis by a direct intracellular inhibition of caspase-3 activation;and (3) To identify whether in patients with emphysema, post-translational alterations in A1AT (oxidation, nitrosylation, or polymerization) impair the anti-apoptotic effect of A1 AT. Discovery of novel mechanisms of intracellular entry and activity of alpha-1 antritrypsin and may provide an opportunity improve our therapeutic approaches in alpha 1 antitrypsin deficiency- and smoking-induced emphysema. We will collaborate closely with Project 4 to determine whether cigarette smoke lung injury in the developing lung life impairs antiapoptotic functions of A1AT. We plan to translate our mechanistic insights of the novel antiapoptotic actions of A1AT in the investigation of posttranslational modifications of A1 AT in patients with COPD (with Project 2) and exposure to environmental particulates (with Project 5) that may render A1 AT inactive against active caspase-3.